Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03121521 |
| Other study ID # |
NN 402 54 37/40 |
| Secondary ID |
RNN/45/12/KB |
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
April 13, 2017 |
| Last updated |
April 19, 2017 |
| Start date |
September 1, 2012 |
| Est. completion date |
December 15, 2016 |
Study information
| Verified date |
April 2017 |
| Source |
Medical Universtity of Lodz |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Introduction. Statins are generally well tolerated but not devoid of side effects. Quite
often it is manifested by asymptomatic increase in the level of aspartate and alanine
aminotransferase. In such cases patients to administer hepatoprotective drugs, but most of
them used for this purpose are ineffective. The aim of this study was assess the usefulness
of melatonin in counteracting the adverse hepatic events from statins. Methods. The research
program included 60 patients(aged 47-65 years, 41 women and 23 men)with hyperlipidemia
taking atorvastatin or rosuvastatin in dose 20-40 mg daily. The patients were randomly
allocated in two groups. Group I (n=30) was recommended to take the same statin at a
standardized daily dose of 20 mg together with melatonin at a dose 2 x 5 mg, at 7:00 and
21:00. In group II (n=30) patients took statins with placebo at the same time of the day.
Follow-up laboratory tests (AST, ALT, GGT, ALP, cholesterol, triglycerides) were evaluated
after 2,4 and 6 mounts of treatment.
Description:
Introduction Statins are widely used in the treatment and prevention of lipid metabolism
disorders. They are generally well tolerated but not devoid of side effects. These include,
among others, muscular symptoms, arthritis, headaches, gynecomastia. Myositis and
rhabdomyolysis associated with increased activity of creatinine kinase and serum creatinine
levels are rare but serious adverse events of statin therapy. The risk of these
complications is increased in elderly patients with chronic diseases and in alcohol abusers.
Furthermore, statins cause hepatotoxic effect which is observed in several percent of
treated patients, usually in the first weeks of the therapy . Most frequently it is
manifested by asymptomatic increase in the level of aspartate and alanine aminotransferase.
This is usually a temporary increase, but in some patients the level of these enzymes
exceeds 3 times the normal limit, which is a matter of concern. In such cases, patients
expect the decision to discontinue the treatment or to administer hepatoprotective drugs.
Acetylcholine, sylibinin, phospholipids and other drugs used for this purpose are not always
effective. Therefore, there is still search for alternative drugs for the protection of
liver.
In own study melatonin was used for this purpose because previous experimental studies had
demonstrated that it protected liver against harmful effects of many toxic agents as well as
the consequences of ischemia-reperfusion model.
The liver is an organ in which there comes to intensive metabolic and detoxification
processes. In their course large amounts of reactive oxygen species are generated and they
exert a toxic effect on hepatocytes. A complex antioxidant system - in which metabolized
there melatonin (pineal and from other sources) is an important part - prevents that.
The main melatonin metabolic pathway in the liver is through hydroxylation pathway at the
C-6 position by 6-hydroxylase and P450 cytochromes (CYP1A1, CYP1A2, CYP2P19, CYP1B1
isozymes). The 6-hydroxymelatonin, formed in this process, is conjugated with sulphate and
glucuronide to 6-hydroxymelatonin sulphate or glucuronide. In this process melatonin and its
metabolites exert high antioxidant activity.
An alternative metabolic pathway includes melatonin oxidation to N-acetyl-formyl-5-
methoxykynuramine (AFMK) and N-acetyl-5-methoxykynuramine (AMK). The kynurenine pathway of
melatonin metabolism leads to formation of a series of free radical scavengers.
Furthermore, melatonin decreases the production of proinflammatory cytokines and inhibits
hepatic fibrogenesis. Owing to its multidirectional action in liver, apoptosis and necrosis
decrease, the integrity is protected and regeneration is improved.
The aim of this study was to assess the usefulness of melatonin in counteracting the adverse
hepatic events from statins.
Material and Methods Patients and Data Collection The research program included 30 subjects,
aged 47-68 years, 41 women and 23 men. All women were I the postpostmenopausal period.
Recruitment and diagnostic tests were conducted in the Department of Gastroenterology,
Medical University of Lodz and Outpatient Consulting Clinic "Gastro" in Lodz.
The research study was performed in the years 2012-2016. Therapeutic Procedures After
inclusion into the study, all patients were recommended the same balanced diet with limited
animal fats and simple carbohydrates of caloric content of 1600 kcal. At the same time, they
were recommended to continue the treatment with the same statin at a daily dose of 20 mg.
The patients were randomly allocated into two groups. Group I (n=30) was recommended to take
statin together with melatonin (LEK-AM, Poland) at a dose of 2x5 mg, at 7:00 a.m. and 9:00
p.m. In Group II (n=30) patients took statin with placebo (LEK-AM, Poland) at the same dose
and time of the day.
Follow-up laboratory tests (AST, ALT, GGT, ALP, cholesterol and triglycerides) were
evaluated after 2,4 and 6 months of treatment.
Ethical procedures A written consent was obtained from the patients and the Bioethics
Committee of the Medical University in Lodz approved the study protocol (RNN/45/12/KB).
Tests were conducted in accordance with the Declaration of Helsinki and with the principles
of Good Clinical Practice.
Statistical analysis All parameters were checked for normality using the Shapiro-Wilk test.
Wilcoxon's rank sum test was used for the comparison of basal treatment differences between
each liver enzyme level. Comparison of parameters in four time series was calculated using
ANOVA Friedman test. Mann-Whitney U test was used for nonparametric data to perform the
comparison between groups. Calculation were made using Statistical 9.1 Microsoft Co.
software, and statistical significance was established at p< 0,05.
Acknowledgments This work was supported by the grant from the Polish Ministry of Science and
Higher Education No: NN 402 54 37/40.
Competing Interests The authors declare that they have no competing interests.
